Low Birth Weight, Catch-Up Growth, & Adipogenesis: Mechanistic Links to Obesity

Joslin Diabetes Center, Boston MA

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): The nutritional environment during both prenatal and postnatal life is increasingly recognized as playing an important role in the pathogenesis of adult disease. Both human and animal studies demonstrate that either under- or overnutrition during critical periods of development are associated with increased risk of type 2 diabetes (1), visceral obesity (2; 3), and cardiovascular disease (4). In addition, rapid postnatal weight gain is also associated with increased susceptibility to obesity and type 2 diabetes (5- 7). The mechanisms involved in this process have yet to be fully determined. Our long-term objective is to further our understanding of the development of obesity and type 2 diabetes in low birth weight mice which would in turn lend insight into the pathophysiology of obesity in humans. Specifically, we propose that the increased adiposity seen in low birth weight mice with catch-up growth is due to increased lipogenesis, impaired lipolysis, and altered differentiation state of adipose tissue. Furthermore, we hypothesize that these differences reflect intrinsic defects which are mediated by epigenetic modifications. To test these hypotheses, we will utilize a mouse model of low birth weight associated diabetes and obesity created in the mentor's lab. Our experiments will focus on the following specific aims: (1) to determine the independent role of prenatal and postnatal nutritional stress on adipocyte function, as assessed by adipocyte size and number, lipogenesis, lipolysis, inflammation, and insulin signaling, (2) to determine whether low birth weight and catch-up growth alter intrinsic differentiation capacity within adipocytes, as assessed by ex vivo differentiation of primary brown preadipocytes. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: Low birth weight, obesity, and type 2 diabetes are major public health challenges in the U.S. and around the world. Unfortunately, the mechanisms that promote obesity and its associated risk of diabetes and cardiovascular disease in low birth weight animals and humans have not yet been defined. While we recognize the limitation of application of rodent data to human disease, further understanding of these mechanisms of obesity may provide increased insight into possible treatments for this serious public health epidemic. [unreadable] [unreadable] [unreadable]